Although regional synthesis of nitric oxide (NO) by the endothelium contributes to local vasodilator tone in the coronary and systemic circulations of healthy subjects, in patients with coronary artery disease, in whom vascular synthesis of NO is reduced or absent, other sources of NO may assume particular importance. In a recently completed study we evaluated the vasodilator properties of nitrite -the reactant product of NO and O2 -in the human forearm and the mechanisms extant for its bioactivation.10 Sodium nitrite was infused at 36 imoles per minute into the forearm brachial artery of 18 normal volunteers, resulting in a regional nitrite concentration of 222 iM and an immediate 175% increase in resting forearm blood flow. Increased blood flow was observed at rest, during NO synthase inhibition and with exercise, and resulted in increased tissue perfusion, as demonstrated by increases in venous hemoglobin-oxygen saturation, partial pressure of oxygen, and pH. Systemic concentrations of nitrite increased to 16 iM and significantly reduced mean arterial blood pressure. In an additional 10 subjects, the dose of nitrite was reduced 2-logs resulting in a forearm nitrite concentration of 2 iM and a 22% increase in blood flow. Nitrite infusions were associated with the formation of erythrocyte iron-nitrosyl-hemoglobin, and to a lesser extent, S-nitroso-hemoglobin across the forearm vasculature. The formation of NO-modified hemoglobin appears to result from the nitrite reductase activity of deoxyhemoglobin, linking tissue hypoxia and nitrite bioactivation. These results suggest that physiological levels of blood and tissue nitrite represent a major bioavailable pool of NO that contributes to vaso-regulation and provides a mechanism for hypoxic vasodilation via reaction of vascular nitrite with deoxygenated heme proteins.